The invention relates to a measurement device for analyzing a sample gas by infrared absorption spectroscopy as well as an according method.
Since centuries it is known that the respiratory odor is an indicator for a possible disease—the most prominent example is the sweetish-fruity odor caused by acetone in diabetes mellitus type I. Even the odor of healthy humans contains several hundred volatile chemical compounds, so-called volatile organic compounds (VOCs) in low concentration (ppm to ppt range). Some of these play an important role in physiological or patho-physiological processes. If a disease is present, the concentration of certain trace gases increases in the breath. In some diseases, also gases can be detected which do not occur in the healthy organism. Thus, the respiratory gas analysis has a big potential for the clinical diagnostics and therapy monitoring. However, the trace gas concentration is often so low that it cannot be measured sufficiently exact with the available gas-analytical methods.
There exist highly sensitive detection methods like e.g. the mass spectroscopy or the FTIR-spectroscopy in multipass sample cells. However, such detection devices cannot be applied directly to a patient and are, consequently, of no relevance for the clinical daily routine. This is also due to the fact that the evaluation needs several days and that non-calculable sources of error occur due to the transport of the samples. Mobile constructions in the area of the infrared absorption spectroscopy having diode lasers (e.g. lead salt lasers) as light sources are also in use since several decades, they could, however, until now not achieve the necessary stability over a longer time period for the sensitive detection of gases so that also in this case the use remained restricted to the medical basic research.
An alternative method is the so-called NDIRS-method (NDIRS-non-dispersive IR spectroscopy). It detects density fluctuations in the sample gas which are triggered by absorption of infrared light. This detection method is sensitive and can perform a measurement every two and a half minutes. However, the measurement results are biassed by other gases like e.g. oxygen so that this method can only be restrictively used in the clinical daily routine.
Another method is used by the company Oridion Systems Ltd. under the denomination BreathID®. Here, a CO2 pressure lamp is used as light source. However, this method is strongly restricted in its sensitivity and speediness by occurring line width fluctuations (in the lamp and in the sample gas), low light intensities and spectral fluctuations and, thereby, does not provide 15 highly sensitive measurement results in short time. The NDIRS method and the method of Oridion Systems Ltd. are well suited for e.g. the detection of the bacterium Helicobacter pylori in the stomach of a patient. The presence of the bacterium is detected in a qualitative manner by an increased 13CO2 content in the exhalation air after application of a 13C-labelled diagnostic.
Qualitative test methods become of no importance if the test lies within the same price segment like the treatment. A further strategy to guarantee the simple and fast detection of volatile chemical compounds is the use of surface-sensitive microchips which select and bind special trace gases from the respiratory air. Thereby, a sensitive detection of these volatile chemical compounds is possible and the qualitative decision whether or not the patient is ill can be made.
The mere detection of a disease is Instructive; however, it does not provide any information on a suited therapy. Thus, the future of respiratory gas analysis lies in the quantitative determination of the degree of disease which offers the physician a direct determination aid for the therapy. If such tests can be carried out simply and quick and the results are immediately present in a comprehensible form for the physician, the test can become accepted in the clinical daily routine.
The requirements for quantitative respiratory gas tests are high: For unambiguously identifying the trace gases, a high selectivity and detection sensitivity is necessary since the concentration lies often in the ppm to ppb range. The exact quantitative determination of the trace gas amount has to be guaranteed. Additionally, the measurements should occur online and in real-time to avoid a laborious and error-prone sample collection (e. g. in bags or in side stream). For a feasible and economic use, simple operation, compactness, robustness, low maintenance effort and/or a favorable cost-benefit ratio are to be required. These high and manifold requirements can currently not be completely met by any gas analytic method.
The exhaled air of humans has a carbon dioxide volume fraction of 2% to 4% and is exhaled in 10 to 20 breaths per minute, by infants and newborns even in 25 to 50 breaths per minute. The respiratory pressure of humans is approximately 50 mbar to maximal 160 mbar, at a volume of approximately 0.5 I. Only approximately 70% of the respiratory air reach the lung so that also in only approximately 70% of the gas volume a significantly increased carbon dioxide fraction is present. In the remaining gas volume—the dead space volume—the carbon dioxide concentration can decrease just onto the concentration of the ambient air of approximately 0.04%. This results in that the carbon dioxide concentration in the respiratory air can fluctuate by 2 orders of magnitude from 0.04% to 4%. Carbon dioxide concentrations of over 5% are toxic and can e.g. lead to headaches and cramps.
The produced carbon dioxide amount depends on the individual metabolism of each single human. Different approximation methods are used to estimate the carbon dioxide production of a human. The influencing parameters are e.g. body weight and body surface. The body surface is in turn often estimated by the body size and the body height so that it is often calculated with only moderately exact parameters in the medical science, strongly restricting a quantitative result evaluation or making it even impossible.
For a direct quantitative determination of metabolism processes or metabolisms it is necessary to track the dynamics of the process in a time-resolved manner, at the best in real time. If the metabolism dynamics exhibits a kinetics which can be modelled by a first order differential equation (first order dynamics), the maximum of the kinetics A and the time constant tau can be determined by solving the differential equation or by fitting an exponential function y(t)=A*exp(−t/tau). Quantitative metabolic parameters can then be determined from the parameters A and tau. Triggering of the metabolism dynamics is at the best achieved by the short-term initiation, e.g. by an i.v. application of a diagnostics or by releasing a diagnostic by a light exposure/irradiation.
If the release or the start of the dynamics takes longer than the slope tau or than a breath, the dynamics of the release has to be separately determined and to be deconvoluted from the metabolism dynamics. An example of a fast metabolism start is the i.v. application of the diagnostic 13C methacetin in bolus. It is distributed with the blood (approximately 60 heart beats per minute) in the body and reaches in approximately I second the liver where it is metabolized to paracetamol and 13CO2. The start of the dynamics is much faster than the respiratory rhythm and thus leads to a first order dynamics which can be directly evaluated. If the SC-methacetin is, however, orally applied, the adsorption in the stomach leads to a convolution of the dynamics with the stomach adsorption dynamics which significantly biases the dynamics.
To monitor the metabolism dynamics in real time, each breath should be measured with a very high sensitivity. This means that the respiratory air in the measurement chamber has to be rapidly exchanged and that a complete evaluation of the breath must have been occurred in less than two seconds.
An analysis method enabling a quantitative determination of the liver function is disclosed in WO 2007/000145 A2. This method is based on a substrate accumulation of the substrate to be metabolized in the liver and the determination of the maximal reaction rate of the substrate, enabling conclusions on the liver function capacity of a patient.
From WO 2007/107366 A1, a generic device for the spectroscopic analysis of a gas is known in which a sample gas continuously flows through a measurement chamber.